Cancer is a crucial disease that becomes a leading cause of death, but the therapeutic needs thereof have not yet been satisfied. In recent years, in order to solve the problem of the conventional chemotherapy in that it affects even normal cells, a cancer treatment using a molecular-targeted agent has been vigorously studied. In this cancer treatment, an agent is designed to target a specific molecule that is specifically expressed in cancer cells, and the cancer is treated with the thus designed agent.
Cadherin is an example of molecules that can be a target of a molecular-therapeutic agent in a cancer treatment. Cadherin is a membrane protein that has been discovered as a molecule that is calcium-dependently associated with homophilic cell adhesion (Yoshida and Takeichi, Cell 28: 217-224, 1982). Proteins that have cadherin repeats (ECs) consisting of approximately 110 amino acid residues having high homology to one another are referred to as cadherin superfamily. There are 120 or more types of such proteins, and they play an important role in the maintenance of a multicellular organization.
An increase in the expression of a cadherin in cancer cells has been reported. With respect to cancer cells in which the expression level of a cadherin in cancer tissues is higher than that in normal tissues, the use of an agent prepared by binding an anticancer agent to an antibody recognizing a cadherin or an antibody having antibody-dependent cellular cytotoxicity (ADCC) for the therapy of cancers has been studied (WO2002/097395 and WO2007/102525).
Based on the characteristics of their structures, proteins belonging to the cadherin superfamily can be broadly classified into (1) classical cadherins, (2) desmosomal cadherins, (3) protocadherins, and (4) other cadherins. Classical cadherins that are main members of the cadherin superfamily are highly homologous to one another (FIG. 1). That is, the classical cadherin is a single transmembrane protein that seems to form a dimer, and it has five cadherin domains of EC1-EC5 in the extracellular region thereof and an intracellular domain. Cell adhesion via such a classical cadherin is characterized in that it is carried out between homologous cells. Cells mutually recognize the same species of cadherin molecules each having different expression status that is specific to cell species, so that cell adhesion is carried out. Homologous cells mutually adhere to each other based on a mechanism whereby an E-cadherin recognizes an E-cadherin and binds thereto and a P-cadherin recognizes a P-cadherin and binds thereto (FIG. 2).
Mutual recognition regarding a homologous/heterologous cadherin is considered to be caused by a cadherin domain 1 (EC1) located at the N-terminus of an extracellular domain (Nose A. et al., Cell 61: 147-155, 1990). Klingel et al. have reported that when the amino acid sequence at positions 1 to 213 of a human P-cadherin (SEQ ID NO: 2) is substituted with the corresponding region of a human E-cadherin, the resultant product does not bind to the E-cadherin but binds to the P-cadherin (Klingel H. et al., J of Cell Science 113: 2829-36, 2000). Hence, classical cadherins including an E-cadherin and a P-cadherin as typical examples are considered to mutually bind to one another by a single same mechanism.
In recent years, a large number of antibody drugs for use in cancer treatments have been actually placed on the market as molecular-targeted agents, and certain therapeutic effects can be obtained. Antibody-dependent cellular cytotoxicity (ADCC) is a main antitumor mechanism of commercially available anticancer agents such as trastuzumab and rituximab, and the increase of the ADCC activity leads to the improvement of therapeutic effects, reduction in side effects, etc. Thus, studies for searching for an antibody having higher ADCC activity and the development of a technique of enhancing ADCC activity have been carried out. For example, there have been developed a technique of removing fucose at the end of a sugar chain binding to the Fc portion of an antibody (WO00/61739) and a technique of substituting amino acids in the Fc portion with other amino acids to enhance affinity for effector cells, so as to increase ADCC activity (WO2008/121160).
As described above, a concept of using an antibody having ADCC activity as a therapeutic agent for cancer is publicly known. However, although there is a report regarding the association of a domain structure with the functions of classical cadherins including a P-cadherin, there are no reports suggesting the association of the level of ADCC activity with the structures of classical cadherins.